Sucrose is not a pain medication

Sucrose is not a pain medication. That rant already exists on this blog. It was also the subject of my talk at the final SMACC conference, which is now online. Another blog post is probably unnecessary, but neither resource included the references from my literature review, so for those who are interested, these are my extended notes on the subject.

Sugar containing solutions have long been used to control pain or calm infants. However, most early solutions were combined with alcohol, cocaine, or opium, and were not subject to rigorous clinical trials, so it is unclear how important the sugar component was. (Harrison 2012)

I don’t think there is much doubt that sucrose changes behaviour, which results in changes on pediatric pain scales. (Stevens 2016) Unfortunately, those scales only measure behaviour, and not (despite their name) pain. (This is explored further below). Objective physiologic changes, such as decreased heart rate, only occur with sucrose in about half the studies. (Stevens 2016)

Infants can’t report their pain, but many other humans can, and sucrose does not reduce pain in anyone who is capable of reporting pain. Sucrose does not reduce pain in toddlers or school aged children. (Harrison 2015) 

Thus, the most accurate summary of the science is that sucrose changes infant behaviour, but does not provide analgesia in any population that can report analgesia.

Sucrose does not consistently change markers of pain

In the original rant, I mentioned two studies by Slater that concluded that although sucrose decreased behavioural “pain” scores, no difference was seen in either EEG or near infrared spectroscopy. (Slater 2010; Slater 2010)

In a similar study, Rioualen (2018) looked at 114 three day old infants undergoing venepuncture, and compared sucrose to breastfeeding. Although the children who received sucrose had lower “pain” scores (based on their behaviour), brain patterns on near infrared spectroscopy were identical between the groups, indicating no change in the cortical sensation of pain.

However, there is one small study that demonstrated better EEG outcomes with sucrose. (Ferdandez 2003) Another recent study used skin conductance as a marker of pain, and also concluded that sucrose helped. (Passariello 2019)

Similarly, cortisol is a marker of stress and increases with pain. Sucrose administration does not decrease salivary cortisol levels in infants undergoing painful procedures, indicating they are just as stressed, whether or not they are given sucrose. (Harrison 2012)

It is important to be clear: imaging studies are not patient oriented outcomes. They also aren’t particularly accurate. However, because infants are nonverbal, we have no access to their subjective sensation of pain, and therefore I think we must assume these tests are correct rather than risk subjecting our most vulnerable patients to needless pain.

Adequacy of “pain” scales

The terms “calming” and “analgesic” are often used interchangeably throughout this literature, but they describe very different effects. Unfortunately, in the non-verbal child, the two cannot be distinguished. (Harrison 2012) Similarly, behavioural responses to fear are no different from those to pain. (Mathew 2003) The difficulty in distinguishing behavioral responses to fear and pain are obvious to any clinician who has sutured a child. They will often scream murder when you haven’t even touched them yet. They look like they are in pain, but the procedure hasn’t even started. The confusion between fear and pain, or analgesia and calming, is the fundamental problem with all of the many pediatric “pain” scores. 

Think about the types of pain that are measured in most of these studies. The heel prick is the classic example. That hurts for sure, but the pain is literally a fraction of a second. Anyone who has had a finger stick glucose knows that it stops hurting almost immediately. So, is measuring the child’s face and crying a couple minutes after the poke a meaningful measure of pain? It might have started with pain, but by 30 seconds it is likely something else. It is more likely to be fear: who the hell are these people poking at me and are they going to do it again?

If you are specifically concerned about pain, and not just distress, these “pain” scales will have at best a decent sensitivity, but a poor specificity because of the many other causes of crying and grimacing in pediatric patients. (Matthew 2003)

Physicians are not very good judges of children’s pain. Neither are parents, although they are probably somewhat better than us. (Singer 2002) However, determining the accuracy of our judgement in infants inherently relies on using subjective pediatric “pain” scales that aren’t directly measuring pain, so it is hard to make any solid conclusions.

Pain scales also tend to fail in exactly the population that needs us most. For a first episode of pain, children are likely to scream, and we are likely to know about it. However, for children who have been through many painful conditions, such as surgeries, PICU admissions, or sickle cell crises, the reaction to pain often changes. Sometimes they just shut down. Crying hasn’t helped the last 20 times, so why bother this time? These patients will be missed by the pediatric “pain” scales, but they are the highest risk population – the exact patients we don’t want to miss. 

Mechanism of action

It is not known how sucrose could control pain, if it does. It seems to require oral administration, because giving it through a gastric tube has no effect. (Ramenghi 1999)

A common theory is that sucrose may increase endogenous endorphins, supported primarily by studies done in rodents, often using significantly higher doses or treating for longer periods of time than we do in humans. (Harrison 2012; Shahlaee 2013) The human evidence is less convincing. One study looked at sucrose in infants born to mothers on methadone. These infants have poorly functioning endogenous opioid systems, and they demonstrated a decreased response to sucrose, which could support the endorphin theory. (Blass 1994) However, another study actually measured endorphin levels after sucrose administration and saw no effect. (Taddio 2003) Furthermore, unlike the animal models, naloxone does not decrease the effect of sweet solutions in infants (in fact, analgesia appeared better with naloxone). (Gradin 2005)

Thus, it isn’t clear if endorphins truly are the mechanism of action. However, if they are, that means that we are trying to produce intrinsic opioids by giving sucrose. If the opioid pathway is the target of sucrose administration, it seems very unlikely that sucrose is the most effective and consistent medication to use. Why not use morphine, or some other proven analgesic? Sucrose has not been compared head to head with any opioid, but I am willing to bet that it is inferior. 

If you are interested in further reading about sucrose’s potential mechanisms of actions, Holsti (2010) is a good start.

Potential harms of sucrose

There may be direct harms from using sucrose, but the available literature is inconclusive because most studies haven’t bothered to look for harms. One study showed an association between an increased number of doses of sucrose and lower scores on motor development and vigor in a group of preterm infants. However, this was a secondary outcome in a trial whose primary outcome showed no difference between the sucrose and water groups. (Johnston 2002) Another study by Carbajal observed slight, transient oxygen desaturations (85%–88%) during 7 of 54 administrations of 0.3 mL of a 30% oral glucose solution for subcutaneous injections in preterm infants, and although not statistically significant, none of the 24 placebo (sterile water) administrations elicited oxygen desaturations. There are also potential dietary concerns regarding early exposure to sugar. (Holsti 2010) Furthermore, because the physiologic effects of sucrose are variable, there are concerns that it will not prevent the long term consequences of repeated pain in neonates. (Fitzgerald 2009; Holsti 2010)

Although I think sucrose is likely to be safe, we should remember that most studies have not specifically looked for harms, and almost no studies look at long term effects after sucrose use, so we really don’t know. The reason that I think sucrose is likely to be safe is the same reason that I think it is unlikely to provide significant pain relief. I don’t think it has significant physiologic effects. However, if you are convinced that sucrose is relieving pain, you are essentially arguing that it has significant physiologic effects, in which case the likelihood of harm increases, and it should be treated like any other drug. 

The real harm of sucrose: other analgesics are not considered

The biggest harm from using sucrose is simply not treating pain with known analgesics. The primary reason I wrote the rant, and gave the talk at SMACC, was my experience of watching multiple children undergo LPs without any local anesthetic. I don’t have data on how often this occurs, but polling the audience at SMACC, the majority of physicians (and most were pediatric specialists) stated that they never used local anesthetics when performing pediatric LPs. Similarly, the twitter response to that talk indicated that some clinicians think it is crazy to even consider using local anesthetics. My primary concern, supported only by my personal observations, is that sucrose makes this worse, by reassuring clinicians that the pain has already been treated, even though we can’t really be sure what effect sucrose is having.

We do not have a great track record when it comes to managing pediatric pain. In fact, historically it was argued that newborn infants did not require any analgesia, and there is even history of surgeries being performed with paralytics but no analgesics or sedatives in the neonatal population. (Walco 1994; Anand 2006; Wilkinson 2012)

I think there is lots of evidence that we undertreat pediatric pain. For example, when 107 preterm infants were studied in a NICU setting over the course of a week, only 3 children were given ANY analgesic. This is despite being given sucrose an average of 68 times each for painful procedures. (Johnston 2002) In other words, we use sucrose as a replacement for real analgesics in the real world. (For more examples of pediatric oligoanalgesia see Simons 2003, Lago 2005, Carbajal 2008, Robb 2017, Dohrenwend 2007, Alexander 2003, Friedland 1997, among many others.)

There are growing concerns about the long term effects of repeated painful experiences in infancy. (AAP 2016) Although sucrose decreases “pain” scores during procedures, it has no effect on the later development of hyperalgesia in infants undergoing repeated painful procedures. (Taddio 2009) Because sucrose does not alter either local release of neurotrophins, nor neuronal pain patterns in the brain, it is very unlikely that it alters the long term effects of repeated pain in infants. (Lago 2014)

I think you get a lot of insight into current practice by just considering how all the sucrose studies are designed. There has been a lot of research recently into whether ketamine is a reasonable analgesic option for emergency department patients. None of those studies were placebo controlled, because we consider it unethical to leave pain untreated. So every single ketamine study has the same design: morphine alone versus morphine plus ketamine. We are trying to figure out if ketamine helps when added to something we already know helps – morphine.

On the other hand, none of the sucrose trials included an active ingredient comparison. Not a single one of these trials gave the children a known analgesic. They were all compared to placebo or no treatment. We left half of the studied children with no treatment at all!

I think that perfectly describes our current pain control in pediatrics. Unlike in adults (who can complain and yell at us), in pediatrics we routinely ignore pain, or under-treat it.

We need to treat children’s pain. Honestly, I don’t really care about sucrose. What bothers me is that sucrose is used as a substitute for, rather than a supplement to, real analgesics.

What am I actually suggesting?

I think sucrose has done a lot of harm. Despite people’s best intentions, I think the use of sucrose has probably increased pain and suffering among our youngest patients. However, if we can come to terms with the fact that sucrose is (probably) not a pain medication, then it might be used safely and effectively as an adjunct.

The question of whether sucrose decreases pain in infants in fundamentally unknowable. Pain is a subjective experience which infants cannot communicate. We know sucrose doesn’t control pain in any human with the ability to communicate about pain, so it would require a tremendous leap (and therefore overwhelming evidence) to assume that it relieves pain only in those people who cannot tell us about their pain. Because sucrose doesn’t control pain in anyone who can report pain, the baseline assumption should clearly be that sucrose is not a pain medication. 

We cannot know definitively if sucrose relieves pain. Any action will be based on an assumption, so we must consider the consequences of our assumptions. If we assume that sucrose is an analgesic, but we are wrong, we will end up causing significant harm by performing painful procedures without analgesia. If we assume sucrose isn’t an analgesic, but we are wrong, all that happens is we choose an alternative, proven analgesic. It is much safer to assume that sucrose is not a pain medication. (Wilkinson 2012)

However, there is significant evidence that sucrose does something. “Pain” scales change when sucrose is given. Because we cannot measure pain, the only scientifically honest conclusion is to report exactly what we are seeing. Sucrose calms babies. It decreases crying and grimacing. Sucrose is not a pain medication, it is a sedative.

Once we come to terms with that fact, we can start using sucrose safely. If an analgesic is required, we should provide an analgesic. We need to immediately stop the barbaric practice of performing neonatal LPs without local anesthetic. No adult patient would allow that to happen. We shouldn’t skip the analgesic step simply because infants can’t complain and they are easy to overpower.

However, if you think the child needs calming, sucrose is a wonderful choice. If you have already anesthetized the child’s back, it is entirely reasonable to add sucrose as an adjunct while you perform an LP.

If I show up to your emergency department with a broken arm and the only analgesia you offer me is a sugar pill, you can expect some very loud complaints. However, if you manage my pain with appropriate analgesics, and then offer me an ice cream (my version of sucrose), I would consider you the best doctor ever.

Sucrose can be used as an adjunct in pediatric pain control, but on it’s own, we must assume that sucrose is not a pain medication.

The SMACC talk:

Other FOAMed

I have a longer post on pediatric pain management, with many alternatives to sucrose, here

Other Notes

There is some evidence that neonates experience pain more intensely than adults. (Fitzgerald 2001; Matthew 2003)

Possible reasons that we neglect pain in infants (from Mattew 2003):

• Lack of awareness of infants’ capability to perceive pain.
• Lack of awareness of clinical situations wherein pain is perceived. 
• Inability of infants to express pain specifically.
• Medical attention focused towards treatment of primary clinical condition.
• Infants’ expression(s) of pain interpreted as expressions of fear.
• Caregivers’ temptation to perform quick procedures without analgesia.
• Reluctance to use analgesics due to side effects.
• Fear of inducing dependence on opioid drugs.
• Lack of awareness of painless routes and methods of analgesia.

Consequences of pain in infants (from Matthews 2003):

• Immediate effects
  • Irritability.
  • Fear.
  • Disturbance of sleep and wakefulness state.
  • Increased oxygen consumption.
  • Ventilation-perfusion mismatch.
  • Diminished nutrient intake.
  • Increased gastric acidity.
• Short term effects
  • Enhanced catabolism.
  • Altered immunological function.
  • Delayed healing.
  • Impaired emotional bonding
• Long term effects
  • Memory of pain.
  • Developmental retardation.
  • Alteration in response to subsequent painful experience.

References

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Alexander J, Manno M. Underuse of analgesia in very young pediatric patients with isolated painful injuries. Annals of emergency medicine. 2003; 41(5):617-22. [pubmed]

Anand KJ, Aranda JV, Berde CB, et al. Summary proceedings from the neonatal pain-control group. Pediatrics. 2006; 117(3 Pt 2):S9-S22. [pubmed]

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Carbajal R, Rousset A, Danan C, et al. Epidemiology and treatment of painful procedures in neonates in intensive care units. JAMA. 2008; 300(1):60-70. [pubmed]

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Friedland LR, Pancioli AM, Duncan KM. Pediatric emergency department analgesic practice. Pediatric emergency care. 1997; 13(2):103-6. [pubmed]

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